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United States Patent | 6,114,356 |
McCullough ,   et al. | September 5, 2000 |
Compositons employing and methods utilizing the optically pure (+) isomer of norcisapride are disclosed. This compound has surprisingly been found to be a potent drug for the treatment of disorders of the central nervous system. The compound, (+) norcisapride, has also been found to be a potent antiemetic agent. Finally, the (+) isomer of norcisapride also avoids certain adverse side effects and certain adverse drug interactions.
Inventors: | McCullough; John R. (Worcester, MA); Jerussi; Thomas P. (Framingham, MA) |
Assignee: | Sepracor, Inc. (Marlborough, MA) |
Appl. No.: | 114319 |
Filed: | July 13, 1998 |
Current U.S. Class: | 514/327 |
Intern'l Class: | A61K 031/445 |
Field of Search: | 514/327 |
4962115 | Oct., 1990 | Van Daele | 514/326. |
5057525 | Oct., 1991 | Van Daele | 514/318. |
5137896 | Aug., 1992 | Van Daele | 514/327. |
5712293 | Jan., 1998 | McCullough et al. | 514/327. |
5739151 | Apr., 1998 | McCullough et al. | 514/327. |
Foreign Patent Documents | |||
0 076 530 B1 | Dec., 1985 | BE. | |
WO 94/01111 | Jan., 1994 | WO. | |
WO 94/01112 | Jan., 1994 | WO. | |
WO 95/01803 | Jan., 1995 | WO. | |
WO 96/40133 | Dec., 1996 | WO. | |
WO 98/03173 | Jan., 1998 | WO. |
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TABLE 1 ______________________________________ Calculated IC.sub.50 Values (.mu.M) at 5-HT.sub.1A and 5-HT.sub.2 Receptors Compound 5-HT.sub.1A 5-HT.sub.2 ______________________________________ (.+-.) Norcisapride 7.48 2.21 (+) Norcisapride 0.0054 0.38 (-) Norcisapride 1.30 -- ______________________________________
TABLE 2 ______________________________________ Calculated IC.sub.50 Values (.mu.M) at 5-HT.sub.1A and 5-HT.sub.2 Receptors Compound 5-HT.sub.1A 5-HT.sub.2 ______________________________________ (.+-.) Cisapride -- 0.26 (+) Cisapride -- 0.0050 (-) Cisapride -- 7.08 ______________________________________
TABLE 3 ______________________________________ IC.sub.50 (nM) Values for Binding to 5-HT.sub.3 and 5-HT.sub.4 Sites Compound 5HT.sub.3 5HT.sub.4 5HT.sub.3 /5HT.sub.4 Ratio ______________________________________ rac-Norcisapride 8.2 686 0.012 (+) Norcisapride 4.5 331 0.014 (-) Norcisapride 30.4 1350 0.023 ______________________________________
TABLE 4 ______________________________________ IC.sub.50 (nM) Values for Binding to 5-HT.sub.3 and 5-HT.sub.4 Sites Compound 5HT.sub.3 5HT.sub.4 5HT.sub.3 /5HT.sub.4 Ratio ______________________________________ rac-Cisapride 365 169 2.2 (+) Cisapride 310 340 0.9 (-) Cisapride 2790 199 14.0 ______________________________________
______________________________________ Tablets Quantity per Tablet in mg. Formula A B C ______________________________________ Active Ingredient 5.0 10.0 25.0 (+) norcisapride Lactose BP 62.0 57.0 42.0 Starch BP 20.0 20.0 20.0 Microcrystalline 10.0 10.0 10.0 Cellulose Hydrogenated Vegetable 1.5 1.5 1.5 Oil Polyvinylpyrrolidinone 1.5 1.5 1.5 Compression Weight 100.0 100.0 100.0 ______________________________________